Cancer cell, 2015-11, Vol.28 (5), p.653-665
- Anderson, Daniel J.
- Le Moigne, Ronan
- Djakovic, Stevan
- Kumar, Brajesh
- Rice, Julie
- Wong, Steve
- Wang, Jinhai
- Yao, Bing
- Valle, Eduardo
- Kiss von Soly, Szerenke
- Madriaga, Antonett
- Soriano, Ferdie
- Menon, Mary-Kamala
- Wu, Zhi Yong
- Kampmann, Martin
- Chen, Yuwen
- Weissman, Jonathan S.
- Aftab, Blake T.
- Yakes, F. Michael
- Shawver, Laura
- Zhou, Han-Jie
- Wustrow, David
- Rolfe, Mark
2015
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- Autor(en) / Beteiligte
- Anderson, Daniel J.
- Le Moigne, Ronan
- Djakovic, Stevan
- Kumar, Brajesh
- Rice, Julie
- Wong, Steve
- Wang, Jinhai
- Yao, Bing
- Valle, Eduardo
- Kiss von Soly, Szerenke
- Madriaga, Antonett
- Soriano, Ferdie
- Menon, Mary-Kamala
- Wu, Zhi Yong
- Kampmann, Martin
- Chen, Yuwen
- Weissman, Jonathan S.
- Aftab, Blake T.
- Yakes, F. Michael
- Shawver, Laura
- Zhou, Han-Jie
- Wustrow, David
- Rolfe, Mark
- Titel
- Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis
- Ist Teil von
- Cancer cell, 2015-11, Vol.28 (5), p.653-665
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2015
- Quelle
- Elsevier ScienceDirect Journals
- Beschreibungen/Notizen
- p97 is a AAA-ATPase with multiple cellular functions, one of which is critical regulation of protein homeostasis pathways. We describe the characterization of CB-5083, a potent, selective, and orally bioavailable inhibitor of p97. Treatment of tumor cells with CB-5083 leads to accumulation of poly-ubiquitinated proteins, retention of endoplasmic reticulum-associated degradation (ERAD) substrates, and generation of irresolvable proteotoxic stress, leading to activation of the apoptotic arm of the unfolded protein response. In xenograft models, CB-5083 causes modulation of key p97-related pathways, induces apoptosis, and has antitumor activity in a broad range of both hematological and solid tumor models. Molecular determinants of CB-5083 activity include expression of genes in the ERAD pathway, providing a potential strategy for patient selection. •CB-5083 is a potent and selective small-molecule inhibitor of the cancer target p97•CB-5083 induced a strong unfolded protein response leading to cancer cell death•CB-5083 has antitumor effects in vivo in multiple myeloma and solid tumor models Anderson et al. characterize CB-5083 as a potent, selective, and orally bioavailable inhibitor of p97, a AAA-ATPase critical for regulating protein homeostasis pathways. CB-5083 activates the apoptotic arm of the unfolded protein response and has antitumor activity in several hematological and solid tumor models.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccell.2015.10.002Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4941640
- Format
- –
- Schlagworte
- Adenosine Triphosphatases - antagonists & inhibitors, Adenosine Triphosphatases - genetics, Adenosine Triphosphatases - metabolism, Animals, Apoptosis - drug effects, Blotting, Western, Cell Line, Tumor, CRISPR-Cas Systems, Endoplasmic Reticulum-Associated Degradation - drug effects, Enzyme Inhibitors - chemistry, Enzyme Inhibitors - pharmacology, Gene Expression Regulation, Neoplastic - drug effects, HCT116 Cells, HEK293 Cells, Homeostasis - drug effects, Humans, Indoles - chemistry, Indoles - pharmacology, K562 Cells, Mice, Nude, Mice, SCID, Molecular Structure, Molecular Targeted Therapy - methods, Neoplasms - drug therapy, Neoplasms - genetics, Neoplasms - metabolism, Nuclear Proteins - antagonists & inhibitors, Nuclear Proteins - genetics, Nuclear Proteins - metabolism, Pyrimidines - chemistry, Pyrimidines - pharmacology, Reverse Transcriptase Polymerase Chain Reaction, RNA Interference, Ubiquitinated Proteins - metabolism, Xenograft Model Antitumor Assays